Method and composition for sterilization of a polymerizable monomer

ABSTRACT

A methods and mixtures are provided for sterilization of a polymerizable monomer, in which the mixture contains at least the polymerizable monomer, a compound (a), and a compound (b). Compound (a) is selected from the group of compounds (a1), compounds (a2), and compounds (a3), wherein compounds (a1) are represented by general formula (I): 
                         
wherein R1, R2, R3, and R4, independent of each other, represent a substituted alkyl residue, a non-substituted alkyl residue, a halogen, a nitro group, or a cyano group; compounds (a2) are selected from the group of dimers of compounds (a1); and compounds (a3) are selected from the group of dialkyldicarbonates. Compound (b) is selected from the group of water and alcohols.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/681,996, filed Nov. 20, 2012, now U.S. Pat. No. 9,457,110, issuedOct. 4, 2016, which claims the benefit of U.S. Provisional PatentApplication No. 61/562,701, filed Nov. 22, 2011, the disclosures ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The invention relates to a method for sterilization of a polymerizablemonomer, in particular to sterilization of a monomer for radicalpolymerization. The invention also relates to mixtures containing apolymerizable monomer, in particular a monomer for radicalpolymerization, a kit for producing bone cement containing one of thesemixtures, and a bone cement paste containing one of these mixtures.

Conventional poly(methylmethacrylate) bone cements (PMMA bone cements)have been known for decades and are based on the ground-breaking work ofSir Charnley (Charnley, J.: “Anchorage of the Femoral Head Prosthesis ofthe Shaft of the Femur.” J. Bone Joint Surg. 42: 28-30 (1960)).

The basic structure of PMMA bone cements has remained the same eversince. PMMA bone cements consist of a liquid monomer component and apowder component. The monomer component generally contains (i) themonomer, methylmethacrylate, and (ii) an activator (e.g.N,N-dimethyl-p-toluidine) dissolved therein. The powder componentcomprises (i) one or more polymers that are made by polymerization,preferably suspension polymerization, based on methylmethacrylate andco-monomers, such as styrene, methylacrylate or similar monomers, (ii) aradio-opaquer, and (iii) an initiator, (e.g. dibenzoylperoxide). Mixingthe powder component and the monomer component, the polymers of thepowder component in the methylmethacrylate swell which generates a doughthat can be shaped plastically. Simultaneously, the activator,N,N-dimethyl-p-toluidine, reacts with dibenzoylperoxide whichdisintegrates and forms radicals in the process. The radicals formedtrigger the radical polymerization of the methylmethacrylate. Uponadvancing polymerization of the methylmethacrylate, the viscosity of thecement dough increases until the cement dough solidifies and thus iscured.

German Patent DE 10 2007 050 762 B3 proposes a kit for producing bonecement comprising two pastes as an alternative to the conventionalpowder-liquid polymethylmethacrylate bone cements. These pastes eachcontain a polymerizable monomer, such as, for example, a methacrylatemonomer for radical polymerization, a polymer soluble in themethacrylate monomer, and a particulate polymer insoluble in themethacrylate monomer. In addition, one of these pastes contains aradical polymerization initiator, whereas the other paste comprises apolymerization activator. As a result of the selected composition, thebone cement produced from these pastes possesses sufficiently highviscosity and cohesion in order to withstand the pressure from bleedinguntil it is fully cured. When the two pastes are mixed, thepolymerization initiator reacts with the accelerator to form radicalsthat initiate the radical polymerization of the methacrylate monomers.Owing to the advancing polymerization, the paste is cured while themethacrylate monomers are consumed. The pastes contained in the kit forproducing bone cement are non-aqueous systems. Accordingly, the pastescontain at most only traces of water.

PMMA bone cements are medical products of class IIb, or medical productsof class III if antibiotics are added. In order to ensure the safety ofthe patients, the PMMA bone cements may be marketed in sterile conditionin a doubly-sterile package only. In conventional PMMA bone cementsconsisting of a liquid monomer component and a powder component, thepowder component is sterilized by subjecting it to ethylene oxide.Sterilization of the powder component by gamma irradiation is customaryas well.

Often used for producing the monomer component, the polymerizablemonomer, methylmethacrylate, is biocidal for most vegetative microbiallife forms due to its lipophilic and thus denaturing properties.Therefore, these micro-organisms cannot exist in anhydrousmethylmethacrylate. However, aside from the vegetative forms,micro-organisms also have generative forms, such as endospores. Thesegenerative survival forms of micro-organisms are formed by gram-positivebacteria, in particular of the Bacillus and Clostridium genus, as ameans of persisting during unfavorable living conditions. In theirresting state, endospores have no active metabolism and possess amulti-layered spore capsule that largely protects the core of the sporefrom the action of chemicals and other environmental effects. Thisrenders spores extremely resistant to the action of heat and chemicals(Borick, P. M.: “Chemical Sterilizers,” Adv. Appl. Microbiol. 10:291-312 (1968); Gould, G. W.: “Recent Advances in the Understanding ofResistance and Dormancy in Bacterial Spores,” J. Appl. Bacteriol. 42:297-309 (1977); Gould, G. W.: “Mechanisms of Resistance and Dormancy,”in Hurst, A. and Gould, G. W. (ed.), The Bacterial Spore, AcademicPress, Inc. New York, 2:173-209 (1983)). Due to their high resistance,endospores are used as bio-indicators for validation and control of theefficacy of sterilization processes. This is based on the assumptionthat the inactivation of endospores is indicative of all vegetativemicrobial forms of life being killed. Endospores of gram-positivebacteria are classified in international resistance class III.Resistance class I includes non-spore-forming bacteria and vegetativeforms of spore-forming bacteria and resistance class II includes sporesthat are killed within a few minutes in a flow of steam at 105° C. Inaccordance with DAB 2008 (Deutsches Arzneimittelbuch—German MedicineBook), all micro-organisms of resistance classes I-III must be killed orinactivated irreversibly.

Accordingly, there is a fundamental need to have methods for efficientsterilization of polymerizable monomers, in particular of monomers forradical polymerization.

Methods for sterilization of polymerizable monomers are known in thefield of medical products. It is common to use physical sterilizationmethods for sterilization of medical products. In particular gammairradiation, electron bombardment, UV irradiation, heat sterilization,and autoclaving with pressurized steam need to be mentioned in thiscontext. However, these sterilization methods are inherentlydisadvantageous due to the extensive use of equipment and processresources required by them. Sterilization of polymerizable monomers bymeans of these physical sterilization methods is inapplicable for otherreasons as well though. For example, subjecting the materials to heat,gamma irradiation or X-ray irradiation would initiate radicalpolymerization of the polymerizable monomers which would result ininadvertent premature curing of the bone cement. Steam sterilization, incontrast, would result in hydrolysis of the polymerizable monomers whichwould prevent polymerization of the polymerizable monomers.

Sterilization of polymerizable monomers is often attained throughsterile filtration and subsequent aseptic packing. However, the asepticproduction of polymerizable monomers is very expensive. Anotherassociated problem is that viruses cannot be removed through sterilefiltration. Moreover, sterilization of pastes for producing bone cementby means of sterile filtration is not feasible due to the high viscosityof the pastes and the radio-opaquers and filling agents contained in thepastes.

Aside from these physical methods, it is customary to use chemicalcompounds for sterilization of medical products. These include, forexample, ethylene oxide, formaldehyde, glutardialdehyde,o-phthaldialdehyde, hypochlorite, chlorine dioxide, peracetic acid, andhydrogen peroxide. However, the use of these compounds is associatedwith significant disadvantages. For example ethylene oxide is sporocidalonly in the presence of moisture such that its use in the absence ofwater does not result in the desired sterilization effect. Moreover,pastes for producing bone cement are usually available in closeddiffusion-tight film pouches or closed plastic cartridges. Ethyleneoxide is incapable of penetrating into these containers; however thepackaged pastes cannot be sterilized by this method. In contrast,aldehydes are usually applied as aqueous solutions or in the gaseousstate in the case of formaldehyde due to their mechanism of action.Peracetic acid and hydrogen peroxide are strong oxidizing agents whichare also used in the form of aqueous solutions. However, for thisreason, these compounds are not suitable for sterilization of mixturesthat must contain only small amounts of water, if any. Chlorine-basedcompounds are usually very effective sterilization agents. They aredisadvantageous though in that chlorine-containing secondary productsremain in the medical product after sterilization.

It is known from pharmaceutical industry that aqueous protein solutions,such as, e.g., vaccines, are very sensitive to the effects of oxidizingsterilization agents and various physical sterilization methods, forexample sterilization with gamma radiation. For this reason, aqueousprotein solutions often have small amounts of the acylating agent,β-propiolactone, added to them for the purpose of sterilization.β-propiolactone can be used inactivate both viruses and spores, inparticular endospores. These effects are likely to occur due toacylation of the amino groups of DNA/RNA or proteins. The water presentas solvent is capable of slowly decomposing β-propiolactone such that noactive β-propiolactone is present any longer in aqueous proteinsolutions after just a short period of time. The principle ofsterilization of aqueous protein solutions by means of acylating agents,such as β-propiolactone, is based on the fact that spores can swell insmall amounts of aqueous media. This swelling renders the double wallsof spores permeable to acylating agents, such that the acylating agentscan penetrate into the spores and be effective therein.

However, swelling of the spores is not feasible in mixtures containing apolymerizable monomer and only small quantities of water, if any.Therefore, swelling cannot be used in preparation of the penetration ofthe acylating agent into spores. Accordingly, sterilization of thesemixtures by means of acylating agents, such as β-propiolactone, appearsnot to be feasible.

BRIEF SUMMARY OF THE INVENTION

The invention is therefore based on providing an effective method forsterilization of a polymerizable monomer, in particular a monomer forradical polymerization. The method is to produce, in particular,mixtures that are free of endospores. Preferably, the method should besuitable for sterilization of polymerizable monomers, in particular ofmonomers for radical polymerization, in mixtures containing no or onlysmall quantities of water, for example no more than 2.0% by weight ofwater, more preferably no more than 1.0% by weight of water, and evenmore preferably no more than 0.5% by weight of water, relative to thetotal weight of the mixture. Moreover, it is preferable for the mixtureto contain no toxic or harmful residues, such as, for example,chlorine-containing residues, after the sterilization is completed.Moreover, it is preferable to also overcome other disadvantages knownfrom the prior art.

Further objects underlying the invention include the provision of amixture (I) that can be used for sterilization according to the methodaccording to the invention, a mixture (II) that can be obtained whilecarrying out the method according to the invention, a kit for producingbone cement that can be obtained after carrying out the method accordingto the invention, and a bone cement paste that can be obtained aftercarrying out the method according to the invention.

Accordingly, the invention provides a method for sterilization of apolymerizable monomer, in particular of a monomer for radicalpolymerization, in which a mixture (I) is produced, the mixture (I)comprising at least the polymerizable monomer, in particular the monomerfor radical polymerization, a compound (a) and a compound (b), wherein:

-   -   (i) compound (a) is selected from compounds (a1) selected from        the group consisting of compounds represented by formula (I):

-   -    wherein R1, R2, R3, and R4 independently represent a hydrogen,        a substituted alkyl residue, a non-substituted alkyl residue, a        halogen, a nitro group, or a cyano group; compounds (a2)        selected from the group consisting of dimers of compounds (a1);        and compounds (a3) selected from the group consisting of        dialkyldicarbonates; and    -   (ii) compound (b) is selected from the group consisting of water        and alcohols;        wherein the fraction of compound (b) in mixture (I) is        preferably no more than 2% by weight, relative to the total        weight of the mixture (I).

The invention also provides a mixture (I), the mixture (I) comprising atleast one polymerizable monomer, in particular a monomer for radicalpolymerization, a compound (a) and a compound (b), wherein:

-   -   (i) compound (a) is selected from compounds (a1) selected from        the group consisting of compounds represented by formula (I):

-   -    wherein R1, R2, R3, and R4 independently represent a hydrogen,        a substituted alkyl residue, a non-substituted alkyl residue, a        halogen, a nitro group, or a cyano group; compounds (a2)        selected from the group consisting of dimers of compounds (a1);        and compounds (a3) selected from the group consisting of        dialkyldicarbonates; and    -   (ii) compound (b) is selected from the group consisting of water        and alcohols;        wherein the fraction of compound (b) in mixture (I) is no more        than 2% by weight, relative to the total weight of mixture (I).

The invention further provides a mixture (II), the mixture comprising atleast one polymerizable monomer, in particular a monomer for radicalpolymerization, and a compound (c), wherein compound (c) is selectedfrom the group consisting of alcohols, carboxylic acids having at leastthree carbon atoms, and esters, and can be obtained by reacting acompound (a) and a compound (b), wherein:

-   -   (i) compound (a) is selected from compounds (a1) selected from        the group consisting of compounds represented by formula (I):

-   -    wherein R1, R2, R3, and R4 independently represent a hydrogen,        a substituted alkyl residue, a non-substituted alkyl residue, a        halogen, a nitro group, or a cyano group; compounds (a2)        selected from the group consisting of dimers of compounds (a1);        and compounds (a3) selected from the group consisting of        dialkyldicarbonates; and    -   (ii) compound (b) is selected from the group consisting of water        and alcohols.

Moreover, the invention provides a kit for producing bone cementcomprising at least one paste A and one paste B, wherein at least one ofpaste A and paste B contains a mixture (II) according to the descriptionprovided herein.

Moreover, the invention provides a bone cement paste containing amixture (II) according to the description provided herein.

The invention is partly based on the surprising finding thatsterilization of a polymerizable monomer, in particular of a monomer forradical polymerization, by an acylating agent according to compound (a)in mixtures is feasible even if the fraction of water in these mixturesis no more than 2% by weight, more preferably no more than 1.0% byweight, and even more preferably no more than 0.5% by weight, relativeto the total weight of the mixture. Although the spores contained in themixture cannot swell at this low quantity of water, the polymerizablemonomer in the mixture is sterilized effectively, which was surprising.

Moreover, another surprising finding is that neither compound (a) northe products obtained by reacting compound (a) and compound (b) inhibitthe polymerization of the polymerizable monomers. This is true also whenfurther components are contained in the mixture being subjected to themethod for sterilization, such as, for example, components of a pastefor producing bone cement.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a method for sterilization of a polymerizablemonomer, in particular of a monomer for radical polymerization.

A polymerizable monomer characterized by sterility is obtained in themethod according to the invention. In the scope of the invention,“sterility” shall be understood to mean a state that is free of viablemicro-organisms. In this context, please refer to the correspondingdefinition provided in EN 556-1:2001.

At least one polymerizable monomer, in particular at least one monomerfor radical polymerization, is being subjected to the method forsterilization.

Polymerizable monomer shall be understood to preferably mean compoundsthat comprise at least one polymerizable olefinic bond. In a broaderscope, the term, polymerizable monomer, shall also be understood to meanmacromers having terminal methacrylate groups, acrylate groups,itaconate groups, maleinate groups or fumarate groups. These macromerscan be liquid or semi-liquid. Moreover, these macromers can be linear orbranched compounds.

The polymerizable monomer, in particular the monomer for radicalpolymerization, used according to the invention preferably has a molarmass of less than 1,000 g/mol. This also comprises polymerizablemonomers that are components of a mixture of monomers, wherein at leastone of the polymerizable monomers of the mixture of monomers has adefined structure with a molar mass of less than 1,000 g/mol.

According to a preferred embodiment, the polymerizable monomer isselected from the group consisting of methacrylic acid esters(preferably mono-functional and multi-functional methacrylic acidesters), acrylic acid esters (preferably mono-functional andmulti-functional acrylic acid esters), methacrylamide, methacrylic acid,acrylic acid, itaconic acid esters, itaconic acid, maleic acid esters,maleic acid, fumaric acid esters, and fumaric acid. The methacrylic acidesters and acrylic acid esters preferably are alkyl esters ofmethacrylic acid and acrylic acid, respectively. In this context, thealkyl group of the alkyl esters preferably has a chain length of 1-10carbon atoms, more preferably a chain length of 1-4 carbon atoms, evenmore preferably a chain length of 1-2 carbon atoms, and most preferablyone carbon atom. According to a particularly preferred embodiment, thepolymerizable monomer is selected from the group consisting ofmethacrylic acid methylester, methacrylamide, and ethylene glycoldimethacrylate.

A mixture (I) is produced for sterilization of the polymerizablemonomer. Mixture (I) preferably is self-sterilizing. A mixture ispreferably said to be self-sterilizing if sterilization does notnecessitate the addition of any further components or the influence ofexternal factors, such as irradiation.

Mixture (I) contains at least one compound (a) aside from thepolymerizable monomer.

Preferably, compound (a) is an acylating agent. Preferably, theacylating agent is capable of acylating amino groups of DNA/RNA orproteins. Compound (a) is therefore capable of killing micro-organismsand thus has a sterilizing effect.

Compound (a) is selected from the group consisting of compounds (a1),(a2), and (a3) according to the description provided herein.

Compound (a) can be a compound (a1) represented by the general formula(I):

In formula (I), R1, R2, R3, and R4 independently represent hydrogen, asubstituted alkyl residue, a non-substituted alkyl residue, halogen, anitro group, or a cyano group.

The stereochemistry of compounds (a1) is not limited in any way.Preferably, the scope of the invention includes all isomers of compounds(a1) represented by general formula (I), regardless of their exactconfiguration.

The alkyl residues can be substituted or non-substituted alkyl residues,independent of each other. At least one substituent of a substitutedalkyl residue is preferably selected from the group consisting ofhalogen residues, nitro residues, and cyano residues.

The alkyl residues can be saturated or unsaturated alkyl residues,independent of each other. Preferably, an unsaturated alkyl residuecomprises at least one carbon-carbon double bond.

The alkyl residues can be branched or unbranched alkyl residues,independent of each other. It is preferable for alkyl residues R1, R2,R3, and R4 to be unbranched alkyl residues.

Independent of each other, the alkyl residues have a main chain lengthin the range of 1-4 carbon atoms, more preferably a main chain length inthe range of 1-2 carbon atoms, and even more preferably one carbon atom.

Fluorine residues, chlorine residues, and bromine residues are preferredhalogen residues in general formula (I). Residues R1, R2, R3, and R4,can represent one or more halogen residues, independent of each other.

According to a preferred embodiment, residues R1, R2, R3, and R4 eachrepresent hydrogen.

According to another preferred embodiment, residue R1 represents amethyl residue and residues R2, R3, and R4 represent hydrogen.

According to another preferred embodiment, residues R1, R2, and R3represent hydrogen and residue R4 represents a methyl residue.

According to yet another preferred embodiment, residues R1 and R3represent hydrogen and residues R2 and R4 represent a methyl residue.

According to a particularly preferred embodiment, compound (a1) isβ-propiolactone (CAS number 57-57-8).

Compound (a) can also be a compound (a2), wherein compound (a2) is adimer of any of compounds (a1). A dimer of compound (a1) is preferablyrepresented by general formula (II):

wherein residues R1, R2, and R3, independent of each other, can have themeanings defined above.

The stereochemistry of compounds (a2) is not limited in any way.Preferably, the scope of the invention includes the use, as compound(a2), of all dimers of compound (a1), in particular of all isomersrepresented through general formula (II), regardless of their exactconfiguration.

According to a particularly preferred embodiment, residues R1, R2, andR3 in formula

(II) each represent hydrogen.

Compound (a) can also be a compound (a3) selected from the groupconsisting of dialkyldicarbonates.

Dialkyldicarbonates can be represented by the following general formula(III):R5-O—CO—O—CO—O—R6  (III).

Residues R5 and R6 can be different from each other or identical.Preferably, residues R5 and R6 are identical.

Residues R5 and R6 can be saturated residues or unsaturated residues,independent of each other. In this context, unsaturated residuescomprise at least one carbon-carbon double bond.

Residues R5 and R6 can be branched alkyl residues or unbranched alkylresidues, independent of each other. Preferably, residues R5 and R6 areunbranched.

Residues R5 and R6 can be substituted alkyl residues or non-substitutedalkyl residues, independent of each other. Halogen substituents, forexample, preferably chlorine substituents, are conceivable assubstituents of residues R5 and R6. Preferably, residues R5 and R6 arenon-substituted.

According to a preferred embodiment, residues R5 and R6, independent ofeach other can have a main chain length in the range of 1-8 carbonatoms, more preferably a main chain length in the range of 1-4 carbonatoms, even more preferably a main chain length in the range of 1-2carbon atoms, and particularly preferably a main chain length of onecarbon atom.

According to a particularly preferred embodiment, compound (a) isβ-propiolactone (CAS number 57-57-8).

Preferably, the fraction of compound (a) in mixture (I) is at least0.0001% by weight, more preferably at least 0.001% by weight, even morepreferably at least 0.01% by weight, and particularly preferably atleast 0.1% by weight, relative to the total weight of mixture (I).

Preferably, the fraction of compound (a) in mixture (I) is no more than50% by weight, more preferably no more than 5% by weight, even morepreferably no more than 2% by weight, and particularly preferably nomore than 0.4% by weight, relative to the overall weight of mixture (I).The fraction of compound (a) in mixture (I) is preferably in the rangeof 0.0001-50% by weight, more preferably in the range of 0.001-5% byweight, even more preferably in the range of 0.001-2% by weight, andparticularly preferably in the range of 0.1-0.4% by weight, relative tothe total weight of mixture (I).

Mixture (I), which is being produced for sterilization of thepolymerizable monomer, also contains a compound (b).

Compound (b) is preferably selected from the group consisting of waterand alcohols. It is preferable for the water to be doubly distilledwater. Preferably, the water is pyrogen-free. The structure of thealcohol is not limited in any way.

Preferably, the alcohol has a main chain length of 1-20 carbon atoms,more preferably a main chain length of 1-10 carbon atoms, and even morepreferably a main chain length of 1-4 carbon atoms.

The alcohol can be a saturated or an unsaturated alcohol. If the alcoholis unsaturated, the alcohol preferably contains at least onecarbon-carbon double bond.

Moreover, the alcohol can be substituted or non-substituted. At leastone substituent of the substituted alcohol is preferably selected fromthe group consisting of halogen substituents, nitro substituents, andcyano substituents.

The alcohol can be a monoalcohol or a polyalcohol. Preferably, thealcohol is a monoalcohol.

The alcohol can be a branched or an unbranched alcohol. Preferably, thealcohol is an unbranched alcohol.

The alcohol is preferably selected from the group consisting of primaryand secondary alcohols.

The alcohol shall preferably be represented by the following generalformula (IV):R7-OH  (IV).

The residue R7 is not subject to any limitation. Preferably, the residueR7 is an alkyl residue. Preferably, the alkyl residue has a main chainlength of 1-20 carbon atoms, more preferably a main chain length of 1-10carbon atoms, even more preferably a main chain length of 1-5 carbonatoms, particularly preferably a main chain length of 1-2 carbon atoms,and particularly preferably a main chain length of 1 carbon atom. Thealkyl residue can be saturated or unsaturated. The residue R7 can besubstituted or non-substituted. Conceivable substituents are, forexample, hydroxyl groups, nitro groups, cyano groups, and halogens. Theresidue R7 can be branched or unbranched.

According to a preferred embodiment, the primary alcohol is selectedfrom the group consisting of methanol, ethanol, ethylene glycol,diethylene glycol, triethylene glycol, tetraethylene glycol, andpentaerythritol. The term primary alcohol shall preferably includepolymerizable monomers, in particular monomers for radicalpolymerization, having alcoholic hydroxyl groups, such as, for example,methacrylic acid-2-hydroxyethylester.

According to another preferred embodiment, the secondary alcohol isselected from the group consisting of isopropanol and butan-2-ol.

According to a particularly preferred embodiment, the alcohol isselected from the group consisting of methanol, ethanol, diethyleneglycol, triethylene glycol, and tetraethylene glycol.

The scope of the invention also includes that the polymerizable monomerand compound (b) in mixture (I) may be the same compound. For examplemethacrylic acid-2-hydroxyethylester can be both the sterilizingpolymerizable monomer and also compound (b).

Preferably, the fraction of compound (b) in mixture (I) is at least0.0001% by weight, more preferably at least 0.001° A) by weight, evenmore preferably at least 0.01% by weight, and particularly preferably atleast 0.1% by weight, relative to the total weight of mixture (I).Preferably, the fraction of compound (b) in mixture (I) is no more than2.0% by weight, more preferably no more than 1.0% by weight, even morepreferably no more than 0.5% by weight, and particularly preferably nomore than 0.4% by weight, relative to the overall weight of mixture (I).The fraction of compound (b) preferably is in the range of 0.0001-2.0%by weight, more preferably in the range of 0.001-1.0% by weight, evenmore preferably in the range of 0.001-0.5% by weight, and particularlypreferably in the range of 0.1-0.4% by weight, relative to the totalweight of mixture (I).

According to a preferred embodiment, the ratio of the quantity ofcompound (b), n_(b), contained in mixture (I) to the quantity ofcompound (a), n_(a), contained in mixture (I) is represented by the inequation n_(b)/n_(a)>0.5, more preferably by the in equationn_(b)/n_(a)>0.8, and even more preferably by the in equationn_(b)/n_(a)>1.

In addition to the polymerizable monomer, compound (a) and compound (b),mixture (I) can optionally contain at least one additional component(d).

The scope of the invention includes, for example, that mixture (I) is apart of a medical product that contains compounds (a) and (b) inaddition to the polymerizable monomer, in particular the monomer forradical polymerization. The scope of the invention includes, inparticular, carrying out the method for sterilization of a polymerizablemonomer in a mixture (I) that contains, aside from compounds (a) and(b), at least one, but preferably all, components that are contained ina kit for producing a bone cement, wherein the component can, forexample, be a paste. Accordingly, mixture (I) can also be a mixturecontaining, aside from compound (a) and compound (b), the components ofa polymethylmethacrylate bone cement that are described in GermanPatents DE 10 2007 052/16, DE 10 2007 050 762 or DE 10 2010 005 956.Moreover, mixture (I) can also be a mixture containing, aside fromcompounds (a) and (b), the components of inorganic bone cements or ofpolymerizable dental materials. Mixture (I) can also be a mixture thatcontains, aside from compound (a) and compound (b), the components of amonomer liquid contained in a kit for producing bone cement (for examplepolymethylmethacrylate bone cement).

Conceivable as additional components (d) are preferably substancesselected from the group consisting of polymers (d1) soluble in thepolymerizable monomer, polymers (d2) insoluble in the polymerizablemonomer, radical polymerization initiators (d3), polymerizationactivators (d4), filling agents (d5), colorants (d6), pharmaceuticalagents (d7), and mixtures thereof.

According to a preferred embodiment, the additional component (d) is apolymer (d1) soluble in the polymerizable monomer. The polymer (d1)soluble in the polymerizable monomer is preferably a polymer having amean molar mass (by weight) of less than 500,000 g/mol and is morepreferably a polymer having a mean molar mass (by weight) of less than150,000 g/mol. The specification of the molar mass refers to the molarmass determined by viscometry. The soluble polymer (d1) can be eithercross-linked or non-crosslinked, and is preferably non-crosslinked. Thesoluble polymer (d1) can be a homopolymer or a copolymer. Preferably,the soluble polymer (d1) is a polymer of a methacrylic acid ester.

According to a particularly preferred embodiment, the soluble polymer(d1) is a copolymer of methacrylic acid methylester. According toanother particularly preferred embodiment, the soluble polymer (d1) isselected from the group consisting of poly(methacrylic acid methylester)(PMMA), poly(methacrylic acid ethylester) (PMAE), poly(methacrylic acidpropylester) (PMAP), poly(methacrylic acid isopropylester),poly(methylmethacrylate-co-methylacrylate), andpoly(styrene-co-methylmethacrylate).

The polymer (d1) is soluble in the polymerizable monomer. According todefinition, the polymer is soluble in the polymerizable monomer if thesolubility of the polymer in the polymerizable monomer at a temperatureof 25° C. is at least 25 g/l, more preferably at least 50 g/l, and mostpreferably at least 100 g/l.

According to another preferred embodiment, the additional component (d)is a polymer (d2) insoluble in the polymerizable monomer. Preferably,the insoluble polymer (d2) is particulate. According to a particularlypreferred embodiment, the insoluble polymer (d2) has an average particlesize in the range of 100 nm-500 μm. The average particle size shall beunderstood herein to mean a size range that applies to at least 90percent of the particles. The insoluble polymer (d2) preferably has amean molar mass (by weight) of at least 150,000 g/mol and morepreferably a mean molar mass (by weight) of at least 500,000 g/mol. Thespecification of the molar mass refers to the molar mass determined byviscometry. The insoluble polymer (d2) can be either crosslinked ornon-crosslinked, and preferably is crosslinked. In this context, thecross-linking is effected through a difunctional compound. Thedifunctional compound can be selected, for example, from the groupconsisting of alkylene glycol dimethacrylates. An expedient cross-linkeris, for example, ethylene glycol dimethacrylate. The insoluble polymer(d2) can be a homopolymer or a copolymer. Preferably, the insolublepolymer (d2) is a polymer of a methacrylic acid ester. According to apreferred embodiment, the insoluble polymer (d2) is a homopolymer or acopolymer of a methacrylic acid alkylester.

According to a particularly preferred embodiment, the insoluble polymer(d2) is selected from the group consisting of cross-linkedpoly(methylmethacrylate-co-methacrylate) and cross-linkedpoly(methylmethacrylate). The insoluble polymer (d2) is insoluble in thepolymerizable monomer. According to definition, the polymer is insolublein the polymerizable monomer, if the solubility of the polymer in thepolymerizable monomer at a temperature of 25° C. is less than 50 g/l, ispreferably less than 25 g/l, is more preferably less than 10 g/l, and iseven more preferably less than 5 g/l.

According to yet another preferred embodiment, the additional component(d) is a radical polymerization initiator (d3).

According to yet another preferred embodiment, the additional component(d) is a polymerization activator (d4). The polymerization activator canbe present in addition to or alternatively to the radical polymerizationinitiator (d3).

According to yet another preferred embodiment, the additional component(d) is a filling agent (d5). Preferably, the filling agent (d5) isselected from the group consisting of inorganic filling agents, organicfilling agents, glass, metals, and carbon. Preferably, inorganic fillingagents are selected from the group consisting of calcium sulfates (suchas calcium sulfate, calcium sulfate dihydrate or calcium sulfatehemihydrate), calcium carbonate, calcium phosphates (such asα-tricalcium phosphate or β-tricalcium phosphate), hydroxylapatite,barium sulfate, and zirconium dioxide. Organic filling agents arepreferably selected from the group consisting of non-crosslinked polymerparticles, cross-linked polymer particles, and polymer fibers. Theglass, as a filling agent, can be present, for example, in the form of aglass powder or in the form of glass fibers. The metal can preferably betantalum or zirconium.

According to yet another preferred embodiment, the additional component(d) is a colorant (d6).

According to yet another preferred embodiment, the additional component(d) is a pharmaceutical agent (d7). Preferably, the pharmaceutical agent(d7) is selected from the group consisting of antibiotics,anti-infective agents, antiseptic agents, antiphlogistic agents, andgrowth factors.

The mixture (I) can be liquid or semi-liquid at room temperature and apressure of 1.013 bar.

According to a preferred embodiment, mixture (I) containing at least thepolymerizable monomer, compound (a) and compound (b), is present in apackage. Preferably, the package is closed. Preferably, the package isdiffusion-tight. The package can, for example, be a cartridge. It isalso possible for the package to be contained in a cartridge. Thecartridge can be part of an application device for bone cement paste.The application device can preferably contain a mixing device. Themixing device can be suitable for mixing individual components of a kitfor producing bone cement to generate a bone cement paste.

A time of action of compound (a) on the polymerizable monomer of atleast 20 minutes, and more preferably of at least 30 minutes, has provento be advantageous for the method according to the invention forsterilization of a polymerizable monomer.

Moreover, it is preferable for the temperature for sterilization of apolymerizable monomer at which compound (a) acts on the polymerizablemonomer in the method according to the invention to be higher than orequal to the melting temperature of the polymerizable monomer.

It is a feature of compound (b) that compound (b) can react withcompound (a). Different products are obtained upon reacting compound (a)and compound (b) depending on the structures of compounds (a) and (b).Surprisingly, the reaction of compound (a) and compound (b) proceeds ata comparatively slow reaction rate in mixtures containing apolymerizable monomer. Therefore, compound (a) first develops itssterilizing effect in mixtures containing compound (b) before reactingwith compound (b). Moreover, the duration of the sterilizing effect ofcompound (a) can be limited by reacting compound (a) and compound (b).

An essential advantage of the method according to the invention forsterilization of a polymerizable monomer is that the sterilizing effectis provided after producing mixture (I) in the absence of any additionalexternal factors. Moreover, it is feasible, for example, to fill asuitable package with mixture (I), where the package is preferablydiffusion-tight. In this context, compound (a) also contacts the insideof the package such that not only the polymerizable monomer andadditional optional components that may be contained in mixture (I) aresterilized, but the inside of the package is sterilized as well.

A mixture (II) can also be obtained by carrying out the method accordingto the invention for sterilization of a polymerizable monomer. Mixture(II) comprises at least one polymerizable monomer. The polymerizablemonomer is preferably a polymerizable monomer according to the precedingdescription in the context of mixture (I). In addition, mixture (II)contains a compound (c). Compound (c) is obtained by reacting compounds(a) and (b), where compounds (a) and (b) are as described above.

The reaction of compounds (a) and (b) preferably proceeds at roomtemperature and without any need for further external measures in theprocess. Different products are obtained upon reacting compounds (a) and(b) depending on the structures of compounds (a) and (b).

If compound (b) in mixture (I) is water and compound (a) is a compound(a1) represented by general formula (I), the method according to theinvention results in the lactone ring being opened to form a carboxylicacid. Preferably, the carboxylic acid obtained by this method isrepresented by general formula (V):HOOC—CR1R2-CR3R4-OH  (V)wherein residues R1, R2, R3 and R4, independent of each other, can havethe meaning defined above.

If compound (b) in mixture (I) is an alcohol represented by generalformula (IV) and compound (a) is a compound (a1) represented by generalformula (I), the method according to the invention results in thelactone ring being opened to form an ester. Preferably, the esterobtained by this method is represented by general formula (VI):R7OOC—CR1R2-CR3R4-OH  (VI)wherein residues R1, R2, R3, R4 and R7, independent of each other, canhave the meaning defined above.

If compound (b) in mixture (I) is water and compound (a) is a compound(a2) represented by general formula (II), the method according to theinvention results in the lactone ring being opened to form a carboxylicacid. Preferably, the carboxylic acid obtained by this method isrepresented by general formula (VII):HOOC—CR1R2-CR3(OH)—CH2-CR3(OH)—CR1R2-COOH  (VII)wherein residues R1, R2, and R3, independent of each other, can have themeaning defined above.

If compound (b) in mixture (I) is an alcohol and compound (a) is acompound (a2) represented by general formula (II), the method accordingto the invention results in the lactone ring being opened to form anester. Preferably, the ester obtained by this method is represented bygeneral formula (VIII):R7OOC—CR1R2-CR3(OH)—CH2-CR3(OH)—CR1R2-COOR7  (VIII)wherein residues R1, R2, R3, and R7, independent of each other, can havethe meaning defined above.

If compound (b) in mixture (I) is water and compound (a) is a compound(a3) represented by general formula (III), the method according to theinvention results in the formation of carbon dioxide and at least onealcohol. Preferably, the alcohol obtained by this method is representedby general formula (IX):R5-OH  (IX)or by general formula (X):R6-OH  (X)wherein residues R5 and R6, independent of each other, can have themeaning defined above.

If compound (b) in mixture (I) is an alcohol represented by generalformula (IV) and compound (a) is a compound (a3) represented by generalformula (III), the method according to the invention results in theformation of carbon dioxide, an alcohol, and an ester. Preferably, thealcohol obtained by this method can be represented by general formula(IX):R5-OH  (IX)or by general formula (X):R6-OH  (X)wherein residues R5 and R6, independent of each other, can have themeaning defined above.

Preferably, the ester obtained can be represented by general formula(XI):R7O—CO—OR7  (XI)wherein residue R7 can have the meaning defined above.

Compound (c) resulting from the reaction of compound (a) and compound(b), is selected from the group consisting of alcohols, carboxylic acidshaving at least three carbon atoms, and esters.

According to a preferred embodiment, the alcohol is selected from thegroup consisting of compounds represented by general formula (V),compounds represented by general formula (VI), compounds represented bygeneral formula (VII), compounds represented by general formula (VIII),compounds represented by general formula (IX), and compounds representedby general formula (X), wherein residues R1, R2, R3, R4, R5, R6, and R7contained therein, independent of each other, can have the meaningdescribed above.

The carboxylic acid is preferably selected from the group consisting ofhydroxycarboxylic acids. Preferably, the hydroxycarboxylic acid is aβ-hydroxycarboxylic acid. According to a preferred embodiment, thecarboxylic acid is selected from the group consisting of compoundsrepresented by general formula (V) and compounds represented by generalformula (VII), wherein residues R1, R2, R3, and R4 contained therein,independent of each other, can have the meaning described above.

The ester is preferably selected from the group consisting ofhydroxyesters and diesters. Preferably, the hydroxyester is aβ-hydroxyester. Preferably, the diester can be a carbonic acid diester.According to a preferred embodiment, the ester is selected from thegroup consisting of compounds represented by general formula (VI),compounds represented by general formula (VIII), and compoundsrepresented by general formula (XI), wherein residues R1, R2, R3, R4 andR7 contained therein, independent of each other, can have the meaningdescribed above.

According to a preferred embodiment, compound (c) is selected from thegroup consisting of compounds represented by general formula (V),compounds represented by general formula (VI), compounds represented bygeneral formula (VII), compounds represented by general formula (VIII),compounds represented by general formula (IX), compounds represented bygeneral formula (X), and compounds represented by general formula (XI),wherein residues R1, R2, R3, R4, R5, R6, and R7 contained therein,independent of each other, can have the meaning described above.

According to a particularly preferred embodiment, compound (c) isselected from the group consisting of 3-hydroxypropionic acid and3-hydroxypropionic acid esters.

Preferably, the fraction of compound (c) in mixture (II) is at least0.0001% by weight, more preferably at least 0.001% by weight, even morepreferably at least 0.01% by weight, and particularly preferably atleast 0.1% by weight, relative to the total weight of mixture (II).Preferably, the fraction of compound (c) is no more than 5.0% by weight,more preferably no more than 2.0% by weight, even more preferably nomore than 1.0% by weight, and particularly preferably no more than 0.5%by weight, relative to the overall weight of mixture (II). The fractionof compound (c) in mixture (II) is preferably in the range of0.0001-5.0% by weight, more preferably in the range of 0.001-2.0% byweight, even more preferably in the range of 0.01-1.0% by weight, andparticularly preferably in the range of 0.1-0.5% by weight, relative tothe total weight of mixture (II).

In addition to the polymerizable monomer and compound (c), mixture (II)can optionally contain additional components (d). These additionalcomponents (d) preferably are the additional components (d) according tothe preceding description in the context of mixture (I).

According to a preferred embodiment, mixture (II) containing at leastthe polymerizable monomer and compound (c), is present in a package.Preferably, the package is closed. Preferably, the package isdiffusion-tight. The package can, for example, be a cartridge. It isalso possible for the package to be contained in a cartridge. Thecartridge can be part of an application device for bone cement paste.The application device can preferably contain a mixing device. Themixing device can be suitable for mixing individual components of a kitfor producing bone cement to generate a bone cement paste.

The invention also provides a kit for producing bone cement, the kitcomprising at least a paste A and a paste B. At least one of pastes Aand B contains one of the mixtures (II) described above. Preferably,paste A and paste B each contain one of the mixtures (II) describedabove, wherein paste A differs from paste B in at least one of itscomponents.

Pastes A and B can contain at least one additional component aside fromthe polymerizable monomer and compound (c). The additional component canbe selected from the group of additional components (d) described above.

According to a preferred embodiment, paste A comprises a polymerizablemonomer, in particular a monomer for radical polymerization, a compound(c), and a polymer (d1) soluble in the polymerizable monomer, and pasteB comprises at least one polymerizable monomer, a compound (c), and apolymer (d1) soluble in the polymerizable monomer. Preferably, at leastone of the pastes A and B also contains a polymer (d2) insoluble in thepolymerizable monomer. A polymer (d2) insoluble in the polymerizablemonomer can also be contained in paste A and paste B. Moreover, at leastone of the pastes A and B contains at least one radical polymerizationinitiator (d3). Preferably, the radical polymerization initiator (d3) iscontained in the same paste that contains the polymer (d2) insoluble inthe polymerizable monomer. Furthermore, it is preferable that at leastone of the pastes A and B comprises a polymerization activator (d4).Moreover, it is preferred that at least one of the pastes A and Bcontains a pharmaceutical agent (d7).

According to a particularly preferred embodiment, paste A and paste Bare present in the kit for producing bone cement in a first package anda second package, respectively. Preferably, the packages are spatiallyseparated from each other. The packages are also preferably closed.Moreover, the packages are preferably diffusion-tight. The packages can,for example, be cartridges. It is also possible for the packages to becontained in cartridges. The cartridges can be part of an applicationdevice for bone cement paste. The application device can preferablycontain a mixing device. The mixing device can be suitable for mixingindividual components of a kit for producing bone cement to generate abone cement paste.

The invention also relates to a bone cement paste. In this context, bonecement shall be understood to mean a paste that can be applied to apatient and can self-harden. The bone cement paste contains a mixture(II) according to the preceding definition.

According to a preferred embodiment, the bone cement paste contains atleast one additional component. The additional component can be selectedfrom the group of additional components (d) described above.

According to a particularly preferred embodiment, the bone cement pastecomprises, according to the invention, aside from the polymerizablemonomer and compound (c), at least one polymer (d1) soluble in thepolymerizable monomer, one polymer (d2) insoluble in the polymerizablemonomer, an optional radical polymerization initiator (d3), an optionalpolymerization activator (d4), and an optional pharmaceutical agent(d7).

EXAMPLES

The invention is illustrated in more detail by the following examples.It is to be understood that the examples do not limit the scope of theinvention.

Examples 1-7 and Reference Examples 1-2 Example 1

A total of 20 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 14 μl distilled water, 10 μl of a 40% ethanolic Bacillussubtilis ATCC 9357 spore suspension were added to each of the screw capvessels. Then 17 μl (20 mg) β-propiolactone were added. The screw capvessels were closed, shaken thoroughly for a short period of time, andstored for seven days at 23° C.

Example 2

A total of 20 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 35 μl distilled water, 10 μl of a 40% ethanolic Bacillussubtilis ATCC 9357 spore suspension were added to each of the screw capvessels. Then 34 μl (40 mg) β-propiolactone were added. The screw capvessels were closed, shaken thoroughly for a short period of time, andstored for seven days at 23° C.

Example 3

A total of 20 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 20 μl methanol, 10 μl of a 40% ethanolic Bacillus subtilisATCC 9357 spore suspension were added to each of the screw cap vessels.Then 17 μl (20 mg) β-propiolactone were added. The screw cap vesselswere closed, shaken thoroughly for a short period of time, and storedfor seven days at 23° C.

Example 4

A total of 20 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 34 μl distilled water, 10 μl of a 40% ethanolic Bacillussubtilis ATCC 9357 spore suspension were added to each of the screw capvessels. Then 34 μl (40 mg) dimethyldicarbonate were added. The screwcap vessels were closed, shaken thoroughly for a short period of time,and stored for seven days at 23° C.

Reference Example 1

A total of 20 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.Then 10 μl of a 60% ethanolic Bacillus subtilis ATCC 9357 sporesuspension were added to each of the screw cap vessels. The screw capvessels were closed, shaken thoroughly for a short period of time, andstored for seven days at 23° C.

Example 5

A total of 8.0 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 14 μl distilled water, 10 μl of a 60% ethanolic Bacillussubtilis ATCC 9357 spore suspension, and 17 μl (20 mg) β-propiolactonewere added to each of the screw cap vessels. The preparations were thenshaken briefly to homogenize the mixture. Then a mixture of 1.0 gzirconium dioxide, 5.5 g of a linearpolymethylmethacrylate-co-methacrylate, and 5.5 g of a cross-linkedpolymethylmethacrylate was added to each of the screw cap vessels. Apaste was thus formed. The preparations were then shaken briefly. Thepreparations were then stored at 23° C. for seven days.

Example 6

A total of 8.0 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 35 μl distilled water, 10 μl of a 60% ethanolic Bacillussubtilis ATCC 9357 spore suspension, and 35 μl (40 mg) β-propiolactonewere added to each of the screw cap vessels. The preparations were thenshaken briefly to homogenize the mixture. Then a mixture of 1.0 gzirconium dioxide, 5.5 g of a linearpolymethylmethacrylate-co-methacrylate, and 5.5 g of a cross-linkedpolymethylmethacrylate was added to each of the screw cap vessels. Apaste was thus formed. The preparations were then shaken briefly. Thepreparations were then stored at 23° C. for seven days.

Example 7

A total of 8.0 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.After adding 20 μl methanol, 10 μl of a 60% ethanolic Bacillus subtilisATCC 9357 spore suspension, and 35 μl (40 mg) β-propiolactone were addedto each of the screw cap vessels. The preparations were then shakenbriefly to homogenize the mixture. Then a mixture of 1.0 g zirconiumdioxide, 5.5 g of a linear polymethylmethacrylate-co-methacrylate, and5.5 g of a cross-linked polymethylmethacrylate was added to saidpreparation in each of the screw cap vessels. A paste was thus formed.The preparations were then shaken briefly. The preparations were thenstored at 23° C. for seven days.

Reference Example 2

A total of 8.0 g methylmethacrylate (Sigma-Aldrich, stabilized withhydroquinone) each were weighed out into five 50 ml screw cap vessels.Then 10 μl of a 60% ethanolic Bacillus subtilis ATCC 9357 sporesuspension were added to each of the plastic bottles. The preparationswere then shaken briefly to homogenize the mixture. Then a mixture of1.0 g zirconium dioxide, 5.5 g of a linearpolymethylmethacrylate-co-methacrylate, and 5.5 g of a cross-linkedpolymethylmethacrylate was added to said preparation in each of thescrew cap vessels. The preparations were then shaken briefly. A pastewas thus formed. The preparations were then stored at 23° C. for sevendays.

Analysis of Examples 1-7 and Reference Examples 1-2

For analysis, the mixtures obtained in the examples and referenceexamples were tested for sterility. For this purpose, two samples weretaken from each screw cap vessel after seven days of incubation. Thesamples were then incubated for 14 days and then tested for sterility inaccordance with ISO11737 part 2. The results are shown in Table 1:

TABLE 1 Test for sterility of the mixtures of examples 1-7 and referenceexamples 1 and 2 in accordance with ISO 11737 part 2. Number of Numberof non-sterile Example sterile samples samples 1 8 2 2 10 0 3 10 0 4 100 Reference example 1 2 8 5 10 0 6 10 0 7 10 0 Reference example 2 2 8

Example 8

In the following, a paste A and a paste B were prepared by mixing theeducts in separate screw cap vessels.

Paste A Educt Weight 1-Cyclohexyl-5-ethyl-barbituric acid 2.0 gMethacrylamide 0.4 g Methylmethacrylate 18.9 g Linearmethylmethacrylate-soluble 6.2 gpolymethylmethacrylate-co-methylacrylate (molar mass < 500,000 g/mol)Cross-linked polymethylmethacrylate (sieve 15.5 g fraction < 100 μm)2,4-Di-t-butyl-4-methyl-phenol 20 mg β-Propiolactone 86 mg Water 86 mg

Paste B Educt Weight Lithium chloride 40 mg2,4-Di-t-butyl-4-methyl-phenol 35 mg Methylmethacrylate 18.9 g Linearmethylmethacrylate-soluble 16.9 gpolymethylmethacrylate-co-methylacrylate (molar mass < 500,000 g/mol)Green lacquer 50 mg Copper(II) hydroxide 2 mg β-Propiolactone 86 mgWater 86 mg

The two pastes were then stored at room temperature for seven days. Then3.5 g of paste A and 3.5 g of paste B were taken and kneaded togetherthoroughly. A green, non-tacky cement dough was thus produced. The doughwas kneaded further by hand. After approximately 2 minutes and 40seconds, the initiation of polymerization was notable by the release ofheat. The end of processability was reached after 4 minutes and 40seconds. The cement dough was fully cured after approximately 6 minutes.

Example 9

In the following, a paste A and a paste B were prepared by mixing theeducts in separate screw cap vessels.

Paste A Educt Weight 1-Cyclohexyl-5-ethyl-barbituric acid 2.0 gMethacrylamide 0.4 g Methylmethacrylate 18.9 g Linearmethylmethacrylate-soluble 6.2 gpolymethylmethacrylate-co-methylacrylate (molar mass < 500,000 g/mol)Cross-linked polymethylmethacrylate (sieve 15.5 g fraction < 100 μm)2,4-Di-t-butyl-4-methyl-phenol 20 mg β-Propiolactone 86 mg Water 86 mg

Paste B Educt Weight Aliquat 336 60 mg (trioctylmethylammoniumchloride)2,4-Di-t-butyl-4-methyl-phenol 35 mg Methylmethacrylate 18.9 g Linearmethylmethacrylate-soluble 16.9 gpolymethylmethacrylate-co-methylacrylate (molar mass < 500,000 g/mol)Green lacquer 50 mg Copper (II) hydroxide 2 mg β-Propiolactone 86 mgWater 86 mg

The two pastes were stored at room temperature for a period of sevendays. Then 3.5 g of paste A and 3.5 g of paste B were taken and kneadedtogether thoroughly. A green, non-tacky cement dough was thus produced.The dough was kneaded further by hand. A release of heat was noted afterapproximately 3 minutes. The end of processability was reached after 4minutes 40 seconds. The cement dough was fully cured after approximately6 minutes and 20 seconds.

Example 10

In the following, a paste A and a paste B were prepared by mixing theeducts in separate screw cap vessels.

Paste A Educt Weight 1-Cyclohexyl-5-ethyl-barbituric acid 2.0 gMethacrylamide 0.4 g Methylmethacrylate 18.9 g Linearmethylmethacrylate-soluble 11.5 gpolymethylmethacrylate-co-methylacrylate (molar mass < 500,000 g/mol)Cross-linked polymethylmethacrylate (sieve 7.7 g fraction < 100 μm)2,4-Di-t-butyl-4-methyl-phenol 20 mg β-Propiolactone 86 mg Water 86 mg

Paste B Educt Weight Aliquat 336 60 mg (trioctylmethylammoniumchloride)2,4-Di-t-butyl-4-methyl-phenol 35 mg Methylmethacrylate 18.9 g Linearmethylmethacrylate-soluble 11.5 gpolymethylmethacrylate-co-methylacrylate (molar mass < 500,000 g/mol)Cross-linked polymethylmethacrylate (sieve 7.7 g fraction < 100 μm)Green lacquer 50 mg Copper (II) hydroxide 2 mg β-Propiolactone 86 mgWater 86 mg

The two pastes were then stored at room temperature for seven days. Then3.5 g of paste A and 3.5 g of paste B were taken and kneaded togetherthoroughly. A green, non-tacky cement dough was thus produced. The doughwas kneaded further by hand. The end of processability was reached after5 minutes. The cement dough was fully cured after approximately 6minutes.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

I claim:
 1. A sterile mixture comprising at least one polymerizablemonomer, an acylating agent, and a compound (b), wherein: (i) theacylating agent is selected from one of compounds (a1), (a2), and (a3),wherein compound (a1) is a compound represented by formula (I):

wherein R1, R2, R3, and R4 independently represent a hydrogen, asubstituted alkyl residue, a non-substituted alkyl residue, a halogen, anitro group, or a cyano group; wherein compound (a2) is selected fromthe group consisting of dimers of compounds (a1); and wherein compound(a3) is selected from the group consisting of dialkyldicarbonates; and(ii) the compound (b) is selected from the group consisting of water andalcohols; wherein a fraction of compound (b) in the mixture is no morethan 2% by weight relative to a total weight of the mixture.
 2. Asterile mixture comprising at least one polymerizable monomer and acompound (c), wherein compound (c) is selected from the group consistingof alcohols, carboxylic acids having at least three carbon atoms, andesters, wherein compound (c) is a reaction product of an acylating agentand a compound (b), and wherein: (i) the acylating agent is selectedfrom one of compounds (a1), (a2), and (a3), wherein compound (a1) is acompound represented by formula (I):

wherein R1, R2, R3, and R4 independently represent a hydrogen, asubstituted alkyl residue, a non-substituted alkyl residue, a halogen, anitro group, or a cyano group; wherein compound (a2) is selected fromthe group consisting of dimers of compounds (a1); and wherein compound(a3) is selected from the group consisting of dialkyldicarbonates; and(ii) the compound (b) is selected from the group consisting of water andalcohols; wherein a fraction of compound (c) in the mixture is no morethan 2% by weight relative to a total weight of the mixture.
 3. Thesterile mixture according to claim 1, wherein the polymerizable monomeris a monomer for radical polymerization.
 4. The sterile mixtureaccording to claim 1, wherein the acylating agent is β-propiolactone. 5.The sterile mixture according to claim 2, wherein compound (c) isselected from the group consisting of 3-hydroxypropionic acid and3-hydroxypropionic acid esters.
 6. The sterile mixture according toclaim 1, wherein the mixture comprises a polymer soluble in thepolymerizable monomer.
 7. The sterile mixture according to claim 1,wherein the mixture comprises a polymer insoluble in the polymerizablemonomer.
 8. A kit for producing bone cement, the kit comprising at leasta paste A and a paste B, wherein at least one of paste A and paste Bcomprises a sterile mixture according to claim
 2. 9. The kit accordingto claim 8, wherein paste A and paste B are present in a first packageand a second package, respectively.
 10. A bone cement paste comprising asterile mixture according to claim 2.